2.1 Cervical Cancer
Worldwide, cervical cancer is the third most common type of cancer in women and the leading malignant tumor of the female reproductive system. It is much less common in the U.S., where the incident rate has been declining due to the use of the Papanicolaou (Pap) smear, which has reduced the death rate from cervical cancer by 70% since its introduction in 1941. Yet according to the American Cancer Society, in the year 2000, 12,800 women were diagnosed with cervical cancer and 4,600 died from the disease.
Cervical cancer is more common in women of low socioeconomic status possibly because they are unable to afford regular Pap smears. Early age at first sexual intercourse, multiple sexual partners, and a large number of pregnancies will increase the risk of a woman getting cervical cancer. Infection with human papillomavirus (HPV), the cause of genital warts, has been strongly implicated in the pathogenesis of cervical cancer; with the discovery of HPV types 16, 18, 31 and 33 in pre-invasive and invasive cervical lesions and HPV type 6 and 11 in benign condylomatous lesions. (Syrjanen et al., 1987, Applied Pathol. 5:121–135). Other risk factors include tobacco use, DES (diethylstilbestro) use during pregnancy, long term use (more than 10 years) of contraceptive pills, weakened immune system, and infections with genital herpes or chronic chlamydia.
The most common symptom of cervical cancer is abnormal bleeding, such as between periods or after intercourse. Often there is also persistent vaginal discharge, which may be pale, watery, pink, brown, blood streaked, or dark and foul-smelling and discomfort during intercourse. However, there are often no symptoms of cervical cancer until the disease is advanced. Even then, symptoms such as loss of appetite, weight loss, fatigue, pelvic, back or leg pain, leaking of urine or feces from the vagina, and bone fracture are vague and nonspecific and may be caused by other diseases. Further, since Pap smears only screen for—but do not diagnose—cervical pre-cancers, the only sure way to tell whether one has cervical cancer is by performing a colposcopy (examination of the cervix), a LASER (a loop electrode), or a biopsy.
There are two main types of cancer of the cervix. The most common is called squamous cell carcinoma, which develops from the flat cells which cover the outer surface of the cervix at the top of the vagina and accounts for 85% of cervical cancers. It is generally accepted that squamous cancers of the cervix develop from preexisting dysplastic lesions. The other type is called adenocarcinoma, which develops from the glandular cells which line the cervical canal (endocervix) leading into the uterus and accounts for 15% of cervical carcinomas. Epidemiologically, cervical adenocarcinoma affects the same patient population as endometrial or ovarian cancer.
The staging of cervical cancer is based on the revised criteria of TNM staging by the American Joint Committee for Cancer (AJCC) published in 1988. Staging is the process of describing the extent to which cancer has spread from the site of its origin. It is used to assess a patient's prognosis and to determine the choice of therapy. The stage of a cancer is determined by the size and location in the body of the primary tumor, and whether it has spread to other areas of the body. Staging involves using the letters T, N and M to assess tumors by the size of the primary tumor (T); the degree to which regional lymph nodes (N) are involved; and the absence or presence of distant metastases (M)—cancer that has spread from the original (primary) tumor to distant organs or distant lymph nodes. Each of these categories is further classified with a number 1 through 4 to give the total stage. Once the T, N and M are determined, a “stage” of I, II, III or IV is assigned. Stage I cancers are small, localized and usually curable. Stage II and III cancers typically are locally advanced and/or have spread to local lymph nodes. Stage IV cancers usually are metastatic (have spread to distant parts of the body) and generally are considered inoperable.
Cervical cancer can be treated with surgery, radiation therapy, chemotherapy, surveillance, adjuvant (additional), or a combination of these treatments. Treatment of cervical cancer depends on the type of cancer, the stage, the size and shape of the tumor, the age and general health of the woman, and her desire for future childbearing.
There are many different types of surgery for cervical cancer. The operation for cancer of the cervix usually involves the removal of the womb (hysterectomy), and sometimes a small part of the vagina and lymph nodes. Radial hysterectomy is associated with a 5-year survival of 90.1%. (Morrow C P and Townsend D E, 1987, Synopsis of Gynecologic Oncology. 3rd ed. New York, N.Y.: John Wiley & Sons Inc. p. 107). A cone biopsy or trachelectomy may be used if the cancerous cells have spread only very slightly beyond the surface cells of the cervix. In certain situations, the ovaries may also be removed but, where possible, they are not taken out in young women as their removal brings on an early menopause. In the most extreme surgery, called a pelvic exenteration, all of the organs of the pelvis, including the bladder and rectum, are removed.
Postoperative radiation is always given in fractionation, to a total dose of 4,500 to 5,000 rads. Even though no survival advantage was shown, radiation therapy appeared to reduce the incidence of pelvic recurrences. Radiation is also used to shrink an especially large tumor prior to surgery or to slow the growth of inoperable tumors using either external beam (similar to an x-ray) or brachytherapy (internal radiation delivered with implanted radioactive seeds). Fatigue is a possible side effect of radiation therapy, but it gradually ceases after treatment is completed.
Short-term chemotherapy, such as hydroxyurea and cisplatin, is used primarily in cases where the disease has spread outside the cervical and where hormonal treatments alone are no longer effective in preventing tumor growth. Potential side effects include nausea and vomiting, loss of hair, low blood cell counts, and fatigue. Many chemotherapeutic drugs have been tried in the past as single agents for the palliation of cervical cancer, but the results were generally disappointing. Nevertheless, the role of chemotherapy in the management of cervical cancer is continually evolving. Oftentimes, chemotherapy with radiation in adjunct to surgery is used. In general, chemotherapy can achieve long-term survival rates of up to 15% to 20%, even in patients with recurrent or metastatic disease (Ali et al., 2000, Oncology 14(8):1223–30). Unfortunately, the high initial response rates to first line chemotherapy does not appear to translate into a survival benefit (Kohno and Kitahara, 2001, Gan To Kagaku Ryoho 28(4):448–53). Moreover, there are many undesirable side effects associated with chemotherapy such as temporary hair loss, mouth sores, anemia (decreased numbers of red blood cells that may cause fatigue, dizziness, and shortness of breath), leukopenia (decreased numbers of white blood cells that may lower resistance to infection), thrombocytopenia (decreased numbers of platelets that may lead to easy bleeding or bruising), and gastrointestinal symptoms like nausea, vomiting, and diarrhea. Active chemotherapeutic agents include cisplatin and fluorouracil (5-FU).
The identification of active chemotherapeutic agents against cancers traditionally involved the use of various animal models of cancer. The mouse has been one of the most informative and productive experimental system for studying carcinogenesis (Sills et al., 2001, Toxicol Letters 120:187–198), cancer therapy (Mallinson, 2001, Lung Cancer 32(3):265–279; Hoffman R M., 1999, Invest New Drugs 17(4):343–359), and cancer chemoprevention (Yun, 1999, Annals NY Acad Sci. 889:157–192). Cancer research started with transplanted tumors in animals which provided reproducible and controllable materials for investigation. Pieces of primary animal tumors, cell suspensions made from these tumors, and immortal cell lines established from these tumor cells propagate when transplanted to animals of the same species.
To transplant human cancer to an animal and to prevent its destruction by rejection, the immune system of the animal are compromised. While originally accomplished by irradiation, thymectomy, and application of steroids to eliminate acquired immunity, nude mice that are athymic congenitally have been used as recipients of a variety of human tumors (Rygaard, 1983, in 13th International Cancer Congress Part C, Biology of Cancer (2), pp 37–44, Alan R. Liss, Inc., NY; Fergusson and Smith, 1987, Thorax, 42:753–758). While the athymic nude mouse model provides useful models to study a large number of human tumors in vivo, it does not develop spontaneous metastases and are not suitable for all types of tumors. Next, the severe combined immunodeficient (SCID) mice is developed in which the acquired immune system is completely disabled by a genetic mutation. Human lung cancer was first used to demonstrate the successful engraftment of a human cancer in the SCID mouse model (Reddy S., 1987, Cancer Res. 47(9):2456–2460). Subsequently, the SCID mouse model have been shown to allow disseminated metastatic growths for a number of human tumors, particularly hematologic disorders and malignant melanoma (Mueller and Reisfeld, 1991, Cancer Metastasis Rev. 10(3):193–200; Bankert et al., 2001, Trends Immunol. 22:386–393). With the recent advent of transgenic technology, the mouse genome has become the primary mammalian genetic model for the study of cancer (Resor et al., 2001, Human Molec Genet. 10:669–675).
While surgery, chemotherapeutic agents and radiation are useful in the treatment of cervical cancer, there is a continued need to find better treatment modalities and approaches to manage the disease that are more effective and less toxic, especially when clinical oncologists are giving increased attention to the quality of life of cancer patients. The present invention provides an alternative approach to cancer therapy and management of the disease by using an oral composition comprising yeasts.
2.2 Yeast-Based Compositions
Yeasts and components thereof have been developed to be used as dietary supplement or pharmaceuticals. However, none of the prior methods uses yeast cells which have been cultured in an electromagnetic field to produce a product that has an anti-cancer effect. The following are some examples of prior uses of yeast cells and components thereof:
U.S. Pat. No. 6,197,295 discloses a selenium-enriched dried yeast product which can be used as dietary supplement. The yeast strain Saccharomyces boulardii sequela PY 31 (ATCC 74366) is cultured in the presence of selenium salts and contains 300 to about 6,000 ppm intracellular selenium. Methods for reducing tumor cell growth by administration of the selenium yeast product in combination with chemotherapeutic agents is also disclosed.
U.S. Pat. No. 6,143,731 discloses a dietary additive containing whole β-glucans derived from yeast, which when administered to animals and humans, provide a source of fiber in the diet, a fecal bulking agent, a source of short chain fatty acids, reduce cholesterol and LDL, and raises HDL levels.
U.S. Pat. No. 5,504,079 discloses a method of stimulating an immune response in a subject utilizing modified yeast glucans which have enhanced immunobiologic activity. The modified glucans are prepared from the cell wall of Saccharomyces yeasts, and can be administered in a variety of routes including, for example, the oral, intravenous, subcutaneous, topical, and intranasal route.
U.S. Pat. No. 4,348,483 discloses a process for preparing a chromium yeast product which has a high intracellular chromium content. The process comprises allowing the yeast cells to absorb chromium under a controlled acidic pH and, thereafter inducing the yeast cells to grow by adding nutrients. The yeast cells are dried and used as a dietary supplement.
Citation of documents herein is not intended as an admission that any of the documents cited herein is pertinent prior art, or an admission that the cited documents are considered material to the patentability of the claims of the present application. All statements as to the date or representations as to the contents of these documents are based on the information available to the applicant and does not constitute any admission as to the correctness of the dates or contents of these documents.